This invention relates to a new, simplified method of preparing a known ketimine compound. Specifically, it is concerned with the synthesis of the (+) enantiomer of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, a critical intermediate in the production of cis-(1S)(4S)-N-methyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline). Sertraline hydrochloride is the active ingredient in the antidepressant Zoloft(copyright).
The most widely used route to date for the commercial preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, leading to cis-(1S)(4S)-N-methyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline), involves a condensation reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone with monomethylamine, which is catalyzed by titanium tetrachloride, as described by W. R. Welch, Jr. et al. in U.S. Pat. No. 4,536,518 and in Journal of Medicinal Chemistry, Vol. 27, No. 11, p 1508, 1984. An alternative method of producing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene ]methanamine is described in U.S. Pat. No. 4,855,500 to J. C. Spavins, wherein the dehydration characteristics of appropriate mesh molecular sieves are employed to promote the condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenone and monomethylamine. The appropriate type molecular sieves (specifically, those having a pore size of about 3 Angstroms) are contacted in situ with the mixture of 4-(3,4dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and monomethylamine, and adsorb the water formed from the condensation reaction.
Substantial economies can be realized by carrying out similar processes to those described in the preceding paragraph, using the optically pure (+) enantiomer of the tetralone starting material, or an optically enriched (+) mixture of the (+) and (xe2x88x92) enantiomers of the same, rather than racemic tetralone. Use of the chiral starting material eliminates the need to resolve the final product and also eliminates the production of intermediates having the undesired sterochemistry.
This invention relates to a process for preparing the optically pure (+) enantiomer of N-[4(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methaneamine, depicted below, 
or an optically enriched (+) mixture of the above compound of formula II and its opposite enantiomer, comprising reacting the optically pure (+) enantiomer of 4-(3,4-dichlorophenyl)-3,4dihydro-1(2H)-napthalenone (xe2x80x9cthe tetralonexe2x80x9d), depicted below, 
or an optically enriched (+) mixture of the (+) and (xe2x88x92) enantiomers of the tetralone, with monomethylamine and either titanium tetrachloride or molecular sieves in a solvent selected from tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), methylene chloride and aromatic solvents such as toluene, xylenes and dichlorobenzene, at a temperature from about xe2x88x9220xc2x0 C. to about 60xc2x0 C., preferably from about 0xc2x0 C. to about 50xc2x0 C.
A more specific embodiment of this invention relates to the process described above, wherein: (a) the ketimine product of formula II that is formed in such process is hydrogenated to form a mixture of cis (+) sertraline (xe2x80x9csertralinexe2x80x9d) and trans (xe2x88x92) sertraline; (b) sertraline is optionally separated from such mixture; and (c) sertraline is optionally converted into its hydrochloride or mandelate salt.
The terms xe2x80x9csertralinexe2x80x9d and xe2x80x9ccis (+) sertralinexe2x80x9d, as used herein, both refer to cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine.
The term xe2x80x9ctrans (+) sertralinexe2x80x9d, as used herein, refers to trans-(1R) (4S)-N-methyl4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine.
The term xe2x80x9ccis (xe2x88x92) sertralinexe2x80x9d, as used herein, refers to cis-(1R) (4R)-N-methyl-4-(3,4dichlorophenyl)-1,2,3,4-naphthaleneamine.
The term xe2x80x9ctrans (xe2x88x92) sertralinexe2x80x9d, as used herein, refers to trans-(1S) (4R)-N-methyl4-(3,4dichlorophenyl)-1,2,3,4-naphthaleneamine.
The term xe2x80x9cracemic cis sertralinexe2x80x9d, as used herein, refers to an optically inactive mixture of cis (+) sertraline and cis (xe2x88x92) sertraline.
The term xe2x80x9cracemic trans sertralinexe2x80x9d, as used herein, refers to an optically inactive mixture of trans (+) sertraline and trans (xe2x88x92) sertraline.
The term xe2x80x9cracemic sertralinexe2x80x9d, as used herein, refers to an optically inactive mixture of racemic cis sertraline and racemic trans sertraline.
The processes of this invention, as well as the use of the ketimine product of such processes in the synthesis of sertraline, are illustrated in the following schemes and described below.
In accordance with the process of this invention, the starting material, optically pure (+) 4(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, or an optically enriched (+) mixture of the (+) and (xe2x88x92) enantiomers of the same compound, is combined with 1.5 to 25 equivalents of monomethylamine and a solvent selected from methylene chloride, THF and aromatic solvents such as toluene, zylenes or dichlorobenzene. Titanium tetrachloride (0.2 to 1.2 equivalents) or molecular sieves is combined with the reaction mixture and reacted at a temperature from about xe2x88x9220xc2x0 C. to about 60xc2x0 C., preferably from about 0xc2x0 C. to about 50xc2x0 C., for about 1 to about 24 hours. Solid by-products (titanium dioxide and monomethylamine hydrochloride) can be removed from the reaction mixture by filtration and washed with the reaction solvent. A suitable filter aid may be utilized to aid filtration. Decolorizing carbon or a suitable filter aid may be added to the solvent containing product, the resulting mixture stirred and filtered off, and the cake washed with the same solvent. 
The solvent containing the (+) ketimine product of formula II, or an optically enriched (+) mixture of the (+) and (xe2x88x92) enantiomers of the same, can then be concentrated by distillation (either atmospherically or under reduced pressure) and then essentially displaced by hexane to a final volume of 3-10 liters per kilogram of starting material. The ketimine product is granulated at a temperature from about at xe2x88x9210xc2x0 C. to about 30xc2x0 C., filtered and washed with hexanes or heptane. Such product can be used directly, solvent wet, in the next step (i.e., the hydrogenation step), or, if needed for storage, it can be dried under vacuum or atmospherically at a maximum temperature of 80xc2x0 C.
If THF is used as the reaction solvent for the ketimine formation reaction, the solvent containing the ketimine product can be concentrated by distillation (either atmospherically or under reduced pressure) and the concentrated solution carried directly into the next step. The dried or solvent wet ketimine product from the above step is combined with THF. The solution is hydrogenated in suitable equipment using up to 30% (weight/weight) of a hydrogenation catalyst such as palladium on carbon water wet catalyst or palladium on calcium carbonate water wet catalyst, or one of the analogous platinum containing catalysts, to produce a mixture of cis (+) sertraline and trans (xe2x88x92) sertraline. The hydrogen pressure for the hydrogenation reaction is from about 1 to about 8 atmospheres, preferably from about 1 to about 5 atmospheres, and the temperature is from about 0xc2x0 to about 70xc2x0 C., preferably from about room temperature to about 60xc2x0 C. The reaction time is generally from about 1 to about 24 hours. The catalyst is then filtered off and washed with the same solvent used for the hydrogenation reaction, and the filtrate is further processed as described below.
If toluene is used as the solvent for the ketimine formation reaction, the solvent containing the ketimine product can be concentrated by distillation (either atmospherically or under reduced pressure) and then hydrogenated, as described above, but using toluene as the hydrogenation solvent, to produce a mixture of cis (+) sertraline and trans (xe2x88x92) sertraline.
The hydrogenation reaction can also be conducted in other solvents such as ethanol, isopropyl ether, methyl t-butyl ether and like solvents, although, depending on the solvent used for the ketimine formation reaction, it may be preferable to isolate the dried ketimine prior to combining it with the hydrogenation solvent. Following completion of the hydrogenation reaction, a filtration is performed to remove the catalyst. Excess monomethylamine is removed via distillation and/or displacement of the original solvent (used for the ketimine formation reaction reaction) with another suitable solvent such as a lower alkanol, tetrahydrofuran, methyl ethyl ketone, or toluene.
The preferred temperature range for the hydrogenation reaction is from about 0xc2x0 C. to about 70xc2x0 C., and the preferred range of hydrogen pressures is from about 1 atmosphere to about 8 atmospheres. The most preferable temperatures are within the range of about room temperature to about 60xc2x0 C., and the most preferable hydrogen pressures are within the range of about 1 atmospheres to about 5 atmospheres.
Preferable catalysts for the reduction or reductive amination described above include platinium, palladium and other precious metal promoters on supports such as carbon, graphite, calcium carbonate or other such supports, all of which are well known in the catalytic hydrogenation industry.
The hydrochloride salt of sertraline can be obtained as follows. Hydrogen chloride, either as a gas or an aqueuous solution, is combined with the filtrate from the hydrogenation reaction and the resulting product is selectively crystallized to isolate cis (+) sertraline (xe2x80x9csertralinexe2x80x9d), granulated at a temperature from about xe2x88x9210xc2x0 C. to 30xc2x0 C., filtered and washed with the reaction solvent. The resulting sertraline hydrochloride salt can be used directly, solvent wet, in further processing, or, if needed for storage, dried at less than 80xc2x0 C., either atmospherically or under reduced pressure.
When toluene is used as the hydrogenation solvent, the sertraline mandelate salt can be formed by combining the filtrate from the hydrogenation reaction with 0.9 to 1.5 equivalents of D-(xe2x88x92)-mandelic acid, at a temperature from about 0xc2x0 C. to about 80xc2x0 C., either directly or as a slurry/solution in ethanol. The resulting product is the sertraline mandelate salt (i.e., the cis (+) sertraline mandelate salt), with only trace amounts of the trans (xe2x88x92) sertraline mandelate. This is because D-(xe2x88x92)-mandelic acid converts both trans-(xe2x88x92)-sertraline and cis (xe2x88x92) sertaline into cis (+) sertraline mandelate (xe2x80x9csertraline mandelatexe2x80x9d). The resulting product is then granulated at a temperature from about xe2x88x9210xc2x0 C. to about 30xc2x0 C., filtered and washed with ethanol. The sertraline mandelate so obtained can then be used directly, solvent wet, in further processing or dried at less than 80xc2x0 C., either atmospherically or under reduced pressure.
The above reaction with D-(xe2x88x92)-mandelic acid can also be carried out in a variety of other solvents (e.g., THF, ethanol, methanol, isopropanol, ethyl acetate, acetone, isopropyl ether, or methyl t-butyl ether), although, depending on the hydrogenation solvent used, it may be preferable to isolate the sertraline free base after the hydrogenation reaction.
As an alternative to concentrating and isolating the solid ketimine product from the ketimine formation reaction, the solvent/ketimine mixture from that reaction can be processed directly forward, without isolation, to the next synthetic step in the production of sertraline, whereby catalytic hydrogenation of the ketimine to form a mixture of cis (+) and trans (xe2x88x92) sertraline is performed using the same solvent. The hydrogenation can be carried out successfully, either after the ketimine formation is complete, or concurrently with the ketimine formation, in a reductive amination manner. The reductive animation approach involves combining the (+) tetralone with monomethylamine (ideally 2.5 to 3.5 mole equivalents) and a suitable hydrogenation catalyst, such as those referred to above, under a hydrogen atmosphere, in a suitable organic solvent such as toluene or THF, until hydrogen uptake ceases or the reaction is otherwise shown to be complete. This reaction is typically carried out at a temperature from about 20xc2x0 C. to about 100xc2x0 C., preferably from about room temperature to about 70xc2x0 C., at a pressure from about 20 psig to about 100 psig, preferably from about 20 psig to about 60 psig. Under these conditions, the (+) tetralone is converted into the corresponding (+) ketimine and immediately reduced to the desired mixture of cis (+) sertraline and trans (xe2x88x92) sertraline.